10alpha methyl, 9beta hormonal steroids



incapable of associating with the receptors.

United States Patent I 100: METHYL, 9,6 HORMONAL'STEROIDS Enghert Harmen Reerink, Pieter Westerhof, and Hendrik Frederik Louis Schiiler, all of Weesp, Netherlands, assignors to North American Philips Company, lnc.,

New York, N.Y., a corporation of Delaware- No Drawing. Filed June 12, 1962, Ser. No. 201,824

, 21 Claims. (Cl. 260-43955) This invention relates to a novel class of steroids which exhibit important pharmacological properties and/or are useful as intermediates in the preparation ofpharmacological active compounds.

This application is a continuation-in-part of our copending application Ser. No. 805,020, filed Apr. 8, 1959, now abandoned.

All the known pharmacologically active steroids of the normal series which'have a methyl substituent at the carbon atom of thenucleus have this substituent in the fl-position. In general these compounds are characterized in having a substantially fiat or planar molecular configuration of the nucleus, with the 10p methyl group projecting'from the plane of the nucleus.

It is now well accepted that the pharmacological activity of the compounds of the normal-series is attributable to the fact that the steroid molecule is capable of conforming to the configuration of the receptor. As a result, those skilled in the. art believed heretofore that steroids of the normal series are highly stereospecific in their interaction with the receptors. of the pharmacologically active compounds of the normal series are substantially flat, it would be expected that the pharmacological activity is connected with a substantially flat structure of the nucleus and therefore it would not be expected that steroids having a Substantially new 1 ,ing, glucocorticoidal, anti-inflammatory, diuretic, etc. .In

planar configuration of the nucleus would possess useful pharmacological properties.

A principal object of our invention is to prepare'a new and novel class of steroids. This and other objects of our invention will be apparent from the description that follows..

Quite unexpectedly, we have discovered a novel class of steroids which behaves contrary to the aforesaid expectations in the steroid art. In contrast to the normal steroids wherein the methyl at the carbon atom- 10 is in the 13 position and the substituent at the carbon atom 9 is in the a position, in our novel class of steroids, the 10 methyl substituent is in the a position while the substituent at the carbon atom 9 is in the B position.

In addition to what has been mentioned above, with respect to the configuration of the 10 methyl group, and the substituent at the carbon atom 9, there is evidence to indicate that the structure of the nucleus of our novel compounds is non-planar. It is suggested that the nucleus of our novel steroids lies in two planes which intersect a a line drawn through the 3th and 9th carbon atoms of the nucleus. While this is a theory and we do not intend to be bound thereby, nevertheless, the indications are strong that the structure of the nucleus is non-planar. Inv

view of the stereo specificity of the receptors, one would expect that such a deviation in the stereochemical structure of the steroid nucleus would render such steroids Consequently, it is surprising that our novel steroids possess any of the pharmacological properties of the steroids of the normal series. I f

l The steroids of our invention even possess a specificity which manifests itself in a fewer number of pharmacological activities than those possessed by the known corresponding compounds of the normal series, and/or exhibit new properties which are not possessed by the corresponding steroid of the normal series. In some cases,

Since, in general, the nuclei Patented Aug. 3, 1965 that-anentirely new class of steroids has-been discovered.

It is believed from all the experimental work accompli'shed to date that the specific 10a methyl 9b configuration of our novel steroids is the common dominant characteristic which produces the tendency for the highly specific actions thereof. Further, in this respect, the 10a methyl, 9,8 configuration of the nucleus in cooperation with the other substituents creates the particular properties possessed by our novel steroids. Hence, the configuration of the nucleus in our novel steroids is dominant with respect to the manner in which they differentiate from the, steroids of the normalseries.

Those novel steroids of the present invention in which the substituents at the carbon atoms 8, 9, 10, 13 and 14 have the same stereo-configuration as those in dihydroisolumister one (lumista-4,22-dien-3-one) are designated hereinafter as retroste'roids." Castells et al., Proc. of the Chemical Society, January 1958, page 7,.has shown that dihydroisolumisterone has the configuration 8b, 9b, 10a methyl, 13b, 14a.

All the novel retrosteroids of the present invention exhibit highly specific pharmacological properties with respect to the following activities: parenteral progestational, oral progestational, pregnancy maintaining, deciduoma-inducing, fertility stimulating, fertility inhibiting, ovulation stimulating, ovulation inhibiting, anti-estrogenic, uterotrophic, anti-uterotrophic, anabolic, renotrophic, anti-androgenic, pituitary stimulating ituitary inhibitgeneral our novel retrosteroids are non-androgenic and non-estrogenic and possess horm onal activity.

With respect to the highly specific pharmacological properties exhibited by the retrosteroids in comparison with the corresponding compounds of the normal series, it will be found that the retrosteroids have fewer or none of the properties in common with the corresponding com; pounds of the normal series and/or the ret-rosteroids may have one or more pharmacological properties which are not possessed by the corresponding compounds of the normal series. In addition the retrosteroids can be unexpectedly superior in one or more of the pharmacological properties which 'are common to the corresponding com pounds of the normal series. One of the outstanding advantages of our novel retrosteroids is that they can be used to produce a desired pharmacological activity with a substantially reduced number of side effects in comparison with the steroids of the normal series. 1 I I To illustrate the differences between our novel retrosteroids and those of the normal series, reference will now be had to comparisons for that purpose.

As previously stated, the retrosteroids of our invention are so different in the scope and specificity of their pharmacological properties that they are not comparable with their corresponding steroids of the normal series. The following examples will make these differences readily apparent.

The compound Epi F of French Patent'1,09 l,734 has no glycogen storage activity and no anti-inflammatory activity while the corresponding retrosteroid of the invention has glycogen storage activity and is not anti-inflammatory.

The l7a-methylandrosta-1,4-diene-17-ol-3-one of British Patent 750,834 is anabolic,.non-parenteral pro'ge'stational, and not pituitary inhibiting. The correspondingretroand pituitary inhibiting.

Androst-4-ene-3,17[3-diol of United States Patent 3 7 2,911,403 is androgenic, anabolic, not pituitary inhibiting, non-thymolytic, non-glucocorticoidal and is not'anti-infiammatory, whereas the corresponding retrosteroid is non-androgenic, non-anabolic, renotrophic, pituitary inhibiting, thymolytic, non-glucocorticoidal and is not antiinilammatory.

The ,7-dehydroprogesterone of United States Patent 2,876,237'is progestationally active and metabolizes androgenic, while the corresponding retrosteroid is antiestrogenic, non-progestationally active, renotrophic and non-androgenic.

17a ethynyland'rosta 4,6 dien-17-ol-3-one of United rectly metabolized. 21-acetoxypregna-4,6-diene-3,ZO-dione of the same patent is weakly parenteral progestationally active, non-orally progestationally active, produces an increase in the Na/K ratio, has no glycogen storage activity, is not anti-inflammatory and is androgenic, whereas the corresponding retrosteroid is orally and parenterally progestationally active, diuretic with no increase in Na/ K ratio, non-androgenic, and is anti-inflammatory. The pregna-l,4,6-triene-3,20-dione has no glycogen storage activity but is parenterally progestationally active but not orally progestationally active and is metabolized androgenic whereas the corresponding retrosteroid is not progestationally active but induces corpora lutea, is pituitary inhibiting and is non-androgenic even if metazolized incorrectly.

The 3,17B-diacetoxyandrosta-3,S-diene of United States Patent 2,885,397 is androgenic, anabolic and is not pituitary inhibiting, whereas the corresponding retrosteroid is non-androgenic, non-anabolic, renotrophic and pituitary inhibiting.

The activities which are mentioned above in connection with the compounds of the normal series are reported in the patents in which such compounds are disclosed.

Many additional comparisons based on our own experiments will be found in Table I following the examples.

In particular the novel steroids of our invention are in the methyl, 9flsteroids which contain at least. 18 carbon atoms in the molecule and wherein any acyclic carbon chain when present and directly attached to the C carbon atom, in the 18 position, contains at least one and not more than five successive carbon atoms.

An important class of these novel steroids of our invention are those in which there is a substituent having a carbon atom directly attached to the C carbon atom which substituent is preferably in the a position. In addition'it is preferred that the substituent atthe carbon atom 14 be in the or. position and that the substituent at the carbon atom 8 be in the 5 position.

More particularly the pharmacologically active steroids of our invention are those designated by the following general formula in which the substituents are designated FORMULA I (R lnb eine wherein R, is a member of the group consisting of carbon to carbon double bonds present at the positions 1, 2, 3 and 4 and n, is a whole number from 0 to 2;

R is a member of the group consisting of carbon to carbon double bonds present at the positions 5 and 6 and 71 is a whole number from 0 to 1.

R is a carbon to carbon double bond present at the position 11 and n is a whole number from 0 to 1;

R is a member of the group consisting of carbon to carbon double bonds present at one of the positions l5, l6 and 17(20), and li is a whole number from 0 to 2;

R is a member of the group consisting of hydrogen, alkyl containing from 1-3 carbon atoms, hydroxy, acyloxy, aralkoxy, alkoxy and acylthio, and

n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms methylene, hydroxymethylene, alkoxymethylcne, the methylene group -CH joining R and R hydroxy, acyloxy, alkoxy, aralkoxy, oxo, F, Cl and Br and n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, alkyl con;

2.- to 3 carbon atoms, alkynyl containing from 2 to 3 carbon atoms, hydroxy, acyloxy, alkoxy and aralkoxy groups, the thio analogues of said hydroxy, acyloxy,

alkoxy and aralkoxy groups, x0, ketalized oxo', F, Cl, Br, -NH

alkyl and -N alkyl H alkyl wherein each alkyl group contains from 1 to 3 carbon atoms and (2,3-d)-isoxazole, (3,2-c) -pyrazole, 2'-methy1'- (3,2-d)-thiozole and 2'-amino-(3,2-d)-pyrimidine heteroeyclic groups wherein each of said heter'ocyclics'is formed by R together with carbon atoms 2 and 3 of the steroid nucleus and R and n is a whole number from 1 to 2; R; is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, acyloxy, aralkoxy, alkoxy, oxo, F, C1 and Br and n is a whole number from I to'2;

R is a member of the group consisting of hydrogen, alkyl containing from I to 3 carbon atoms, hydroiiy, acyloxy, alkoxy, acylthio, aralkoxy, F, Cl and Br and n is a whole number from 0 to 1;

R is a' rnember of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, methylene, trifluoromethyl, trichloromethyl, tribromom'ethyl, alkeriyl containing from 2 to 3 carbon atoms, alkynyl containing from 2 to 3 carbon atoms, hydroxy, acyloxy, allioxy, aralkoxy, acylthio, 0x0, nitro, amino, F, Cl and Br and n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen,

alkyl containing 1 to 3 carbon atoms, hydroxy, acyloxy, acylthio, alkoxy, aralkoxy, oxo, amino, F, C1 and Br, and

n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, hydroxy, acyloxy, alkoxy and aralkoxy and R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, acyloxy, alkoxy, aralkoxy, F, Cl and Br and R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, methylene, alkenyl containing from 2 to 3 carbon atoms, alkynyl containing from 2 to 3 carbon atoms, hydroxy, acyloxy, alkoxy, aralkoxy, oxo, amino, F, Cl and Br and n is a whole number from 1 to 2;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, ac'yl oxy, alkoxy, aralkoxy, oxo, F, Cl and Br and rt is a whole number from 1 to 2; I

R is a member of the group consisting of hydrogen, methyl hydromethyl, formyl and together with R the'radical I wherein the carbon atom of said radical is connected to the'carbon atom 13 and the oxygen atom is connected to carbon atom 11;

R is a" member of the group consisting of hydrogen,

'alkyl containing from 1 to 3 carbon atoms, hydroxy,

acyloxy, alkoxy andaralkoxy and R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, hydroxy, acyloxy, alkox'y, a'ralltoxy, oxo, F, Cl and Br and m is a whole number from 1' to 2;

R is a member of the group consisting of hydrogen, alkyl containing from 1 to 3 carbon atoms, methylene, trifluorme'thyl, trichlorome'thyl', tribromomethyl, alkenyl containing from 2 to 3 carbon atoms, alkynyl containing from 2 to 3 carbon atoms, hy'clroxy-methylene, hydroxy, acyloxy, alkoxy, aralkoxy, oxo, amino, F, Cl and Br and n is a whole number from Ito 2';

R1 is a member of the group consisting of hydrogen, hydroxy, acyloxy, alkoxy, aralkoxy, thio-analogues of said hydroxy, alkox'y and aralkox'y groups, alkyl containing from 1 to 6 carbon atoms, alkenyl containing from 2 to 6 carbon atoms, alkynyl containing from 2 to 6 carbon atoms, and said alkyl', alkenyl and alkynyl groups substituted with at least one member of the group consisting of hydroxy-, hydroxy esterified with inorganic acid, hydroxy esterified with inorganic acid of which one of the hydrogen atoms is replaced by an alkali metal atom, acyloxy-, alkoxy-, aralkoxy-, oxo-, amin'o-, F-, Cl-,

Brand the thio analogues of said hydroxy, alkoxy and ar'alkoziy groups and R' is a member of the group consisting of hydrogen, hydroxy, acyloxy, alkoxy, aralkoiiy, thio-analogues of said hydroxy, alkoxy and aralkoxy groups, F, Cl, Br, alkyl containing from 1-6 carbon atoms, alkenly containing from 2-6 carbon atoms, alkynyl containing from 2-6 carbon atoms, said alkyl, alkenyl, and alkynyl groups substituted with at least one member selected from the group consist ing of hydroxy-, acyloxy-, alkoxy-, aralkoxy-, the thioanalogues of said hydroxy, alkoxy and aralkoxy groups, carboxy-, oxo-, amino-, F, Cl and Br, the oxo group joining R and R;-,, the group CH joining R and R and a spirolactone containing from 3-6 carbon atoms joining R and R'n, a ketal group joining R and R and a ketal group joining R' and R An interesting groupof the hormonal retrosteroids of our invention are the 10st methyl steroids corresponding to the general structural formula:

FORMULA 11 Fi e (Rai R is a substituent selected from the group consisting of hydrogen and the methyl radicals and n is a whole number from 1 to 2;

R, is a substituent selected from the group consisting of hydrogen, methyl, ethyl, hydroxy, etherified hydroxy and esterified hydroxy radicals and n is a whole number from 1 to 2 R is a substituent Selected from the group consisting of keto, hydroxy, esterified hydroxy and etherified hydroxy radicals and n is a whole number from 1 to 2;

R is a substitucnt selected from the group consisting of hydrogen, chlorine and fluorine and n is a whole number from 1 to 2;

R is a substituent selected from the group consisting of hydrogen, bromine, chlorine, fluorine, hydroxy, methyl, etherified hydroxy and esterified hydroxy radicals and n is a whole number from 1 to 2;

R is asubstituent selected from the group consisting of hydrogen, bromine and fluorine and R is a substituent selected from the group consisting of hydrogen, the hydroxy radical and keto radicals and 11 is a whole number from 1 to 2;

R is a substituent selected from the group consisting of hydrogen, hydroxy, etherified hydroxy, esterified hydroxy and ethyl and methyl radicals and n is a whole number from 1 to 12 R and R are each selected from the group consisting of hydrogen, aliphatic hydrocarbon radicals containing from 1-6 carbon atoms, hydroxy derivatives of said aliphatic hydrocarbon radicals, etherified hydroxy derivatives of said aliphatic hydrocarbon radicals, esterified hydroxy derivatives of said aliphatic hydrocarbon radicals and keto derivatives of said aliphatic radicals, and jointly the keto radical with the proviso that at least one of the substituents defined by R and R' being a substituent other than hydrogen.

R is a carbon to carbon double bond present at at least one of the positions 1, 2, 3, 4 and n is a whole number from -2;

R is a member of the group consisting of carbon to carbon double bonds present at the positions 5, 6, 7 and 8 and n is a whole number from 0 to 2;

R is a member of the group consisting of carbon to carbon double bonds present at the positions 8(14) and 9(11) and n is a whole number from 0 to 2;

R is a member of the group consisting of carbon to carbon double bonds present at one of the positions 15 and 16 and n is a whole number from 0 to 2.

A particular group of compounds of Formula II are those in which there is a conjugated carbon double bond system at the carbon atoms and 7 of the steroid nucleus.

Referring to the general Formula I, three particular groups of retrosteroids having female hormonal activity are those in which all substituents are the same as defined therein except that:

Group A-Ry; is

and R is H.

Group B-R is OR wherein R is hydrogen, alkyl or acyl and R is alkyl of 2 6 carbon atoms, alkenyl or alkynyl each of 26 carbon atoms.

Group CR17 is and R' is OR" wherein R" is acyl.

With respect to the retrosteroids of these formulae having female hormonal activity they have at least one of the following pharmacological activities namely, oral and/or parenteral progestational, anti-progestational, uterotrophic, anti-uterotrophic, anti-estrogcnic, fertility stimulating, fertility inhibiting, anti-arteriosclerosis, corpora lutea induction, ovulation inhibiting and/or ovulation stimulating activities. In addition some of these compounds may have anti-tumor, pituitary stimulating and/or pituitary inhibiting activities.

As to the compounds falling within the groups A, B and C, the introduction of a double bond at the carbon atom number 1 has a tendency to decrease progestational activity and to enhance ovulation stimulating activity. The presence of .a keto group at carbon atom number 3 and a double bond at carbon atom 4 has a tendency to enhance oral and parenteral progestational activity as compared with the same activity of the corresponding compound of the invention in which such a keto atom and such a double bond are absent.

The presence of a keto group at carbon atom number 3 and double bonds at carbon atom numbers 4 and 6 has a tendency to enhance oral and parenteral progestational activity and anti-uterotrophie activity as compared with the same activities of the corresponding compound of the invention in which such a keto group and such double bonds are absent. The presence of an alkoxy or acyloxy group at carbon atom number 3 and double bonds at carbon atom 3 and 5 have a tendency to decrease the intensity of progestational activity but prolong the same as compared with the same activities of the corresponding compound of the invention in which such alkoxy, acyloxy and double bonds are absent. A fluoro or chloro atom at carbon atom number 6 has a tendency to increase any female hormonal activity already possessed by the compound. A double bond at carbon atom number 7 has a tendency to decrease any female hormonal activity already possessed by the compound but to enhance antiar-teriosclerotic activity.

Referring to the Formula I three particular groups of retrosteroids having male hormonal activity are those in which all substituents are as defined therein except that Group DR17 is hydrogen, or OR, wherein R is hydrogen or acyl and R is hydrogen or OR, wherein R is hydrogen or acyl, provided that R and R' are neither both hydrogen nor both OR.

Group ER and R together form the oxo group. Group F-R is OR wherein R is hydrogen, alkyl or acyl, and R' is methyl.

The compounds falling within the above groups D, E x

and F possess at least one of the following pharmacological activities, namely, anti-androgenic, anabolic, renotrophic, anti-catabolic, catabolic, increase or decrease of spermatogenesis and/or anti-anemic activities.

In addition some of these compounds may have antitumor, pituitary stimulating and/or pituitary inhibiting activities.

With regard to the compounds falling within the groups D, E and F the combination of a keto group at the carbon atom number 3 with a double bond at carbon atom numbet 4, has a tendency to enhance anabolic and/or renotrophic activities. The combination of a keto group at carbon atom number 3 with double bonds at carbon atoms 4 and 6 in the compounds falling within the Groups D, E and F tends to impart anti-androgenic and/or pituitary inhibiting activities. A halogen atom especially a fluorine or chlorine atom at the carbon atom number 6 in compounds falling within the Groups D-F has a tendency to increase the anabolic activity.

Referring to Formula I, particular groups of retrosteroids having cortiocoidal activity are those in which all substituents are as defined thereinexcept that Group G-R is and R is hydrogen; Group H-R is and R' is OR;

Group Ione of the 'substituents at carbon atom 11 is hydroxy,

o Rn is Ji-C rnon and 'R' is OR and wherein in these groups G, H,

I, I, R is hydrogen oracyl.

The compounds falling within the G, H, I and J Groups possess at least one of the following properties, namely, gluco-corticoid, anti-glu'co-corticoid, anti-inflammattory, mineralo-corticoid, anti-mineralo-corticoid, diuretic, anti-diuretic, anti-allergic, and/or anti-diabetic activities.

In addition some of these compounds may have antitumor, pituitary stimulating and/or pituitary inhibiting activities. 7

The presence of a keto group at carbon atom number 3 and an olefinic double bond at carbon atom number 4 has a tendency to enhance one or more of the corticoidal activities of the retrosteroids falling within the Groups G, H, I and J as compared with the corresponding activities of the corresponding compounds of the invention in which such a keto group and such a double bond is absent. Introduction of another olefinic double bond at carbon atom number 6, in addition to the keto group at carbon atom number 3 and the double bond at carbon atom number 4, has a tendency to enhance the corticoidal activity still further as compared with the corresponding activities of the corresponding compound of the invention in which such a double bond is absent.

In general, the activity of the retrosteroids of the Groups A-J inclusive of the present invention show a tendency to be enhanced by the introduction of a double bond at carbon atom number 6, as compared with the corresponding activity of the corresponding compound of the invention in which such a double bond is absent.

The following structural formulae (K, Land M) represent compounds having at least progestational and antiuterotrophic properties.

'10 wherein R is an olefinic double bond at carbon atom 6, n =0-1, R is hydrogen, F, C1 or Br, n =1-2, when n is 2, R comprises two hydrogen radicals or one hydrogen and one halogen radical, and R' is hydrogen or acyloxy.

wherein R is alkoxy or acyloxy, is hydrogen, F or Cl, and R' is hydrogen or acyloxy.

R is hydrogen or acyl, R5 is an olefinic double bond at the carbon atom 6 and rr5= 01 anaR' is alkyl of 1-6 carbon atoms, alkenyl of 2 6 carbon atoms or alkynyl of.2-6 carbon atoms.

The following structural Formula M represents compounds having progest'ation'al, d'eciduomata inducing and fertility inhibiting activities:

carbon 23 6-dehydro-6-fluoro-1 7 a-allyl-retro-testosterone 6dehydro-6-fiuoro-17a-allyl-retro-testosterone 17-acetate 3-ethylenolether of 17 a-allyl-retro-testosterone An important class of the novel steroids of cur invention are those that serve as intermediates for the preparation of our novel hormonally active retro-steroids.

One group of these intermediates is those having the same structure as Formula I in respect to all the substituents except that n,, is a whole number from to 2, R' is hydrogen and R is the group CH3 QIV wherein Q is an alkyl of 13 carbon atoms, phenyl, the group \R wherein R and R are both alkyl or the cyclic group RIII wherein R" and R' form together a bivalent hydrocarbon radical and Q is phenyl, hydrogen or alkyl of 1-3 carbon atoms with the proviso that Q is hydrogen when Q contains nitrogen and Q is an alkyl group of 1-3 carbon atoms but not more than three carbon atoms together with Q, when Q is alkyl.

Another group of these novel intermediates are those which also have the same structure as Formula I in respect to all the substituents except that n is a whole number from 0 to 2 and R together with R' is the group x (ii-OC=0 I wherein X is the carbon atom 17 of the nucleus.

Other novel intermediates are those similar to the above two groups and Formula I but in which there are present a double bond at 8 (9) or 9 (11) and/or one or more epoxy groups joining the following pairs of nuclear carbon atoms: 1,2; 4,5; 5,6; 6,7; 9,11; 11,12; 14,15 and 16,17.

The use of these novel steroids of our invention in the preparation of our novel hormonally active retro-steroids will be apparent from the description of the methods of preparing these retro-steroids which follows:

We may start with steroids already containing the m methyl 9;; configuration such as lumisterol 2 or lumisterol 3.

Also the IOa-methyl, 9;? configuration of the retrosteroids of our invention may be prepared by irradiation with ultraviolet light of certain normal steroids having a A configuration in the same manner that ergosterol and 7-dehydrocholesterol are converted into lumisterol 2 and lumisterol 3, respectively.

Thus, irradiation (preferably with ultraviolet light) of 5,7-bisdehydro-normal steroids, having the IO-methyl group in 19 position, a hydrogen atom at carbon atom 9 in a position, a substituent at carbon atom 13 in 3 position and a substituent at carbon atom 14 in a position, followed by eliminations of the double bond between carbon atoms 7 and 8 produces steroids having a nucleus of which the configuration at the carbon atoms 10, 9, 8, 13 and 14 is that of the nucleus of our novel retro-steroids (10o: methyl, 918, 13B, 140:).

In this manner, the 100: methyl, 9;? configuration in the novel steroids of our invention, can be introduced as set out in the foregoing paragraph. The starting materials used in the irradiation process may already contain the substituents as set out in Formula I. However, sometimes the presence of certain light absorbing chemical systems other than the 5,7-bisdehydro system may disturb the conversion into our novel 10:: methyl, 9,8 steroids.

In principle this method of introducing the methyl, 9,8 configuration by irradiation with ultraviolet light may be applied to all normal steroids (those containing a 10,8 methyl, 9a configuration) with two limitations. One of these limitations is that there be no substituent present providing steric hindrance of the IO-methyl group. It is particularly important that the substituents present on the 1, 9 or 11 positions of the steroid molecule do not sterically hinder the 10methyl group. Also there must be no sub stltuents which have a natural absorption between 220 and 330 mg or materially influence the absorption of the A system. Thus no non-ketalized keto group or one.

or more double bonds in conjugation with the A sys tem may be present.

Starting products for the preparation of the retro-steroids according to the invention may be, for example, those natural sterols which have a saturated or unsaturated aliphatic carbon chain, such for example ergosterol.

Alternatively, the starting products may be found in the classes of the sapogenines, which have a heterocyclic group in the side chain, for example diosgenine. In both cases the A-"-"-system should be provided for the radiation if it is not already present in the molecule.

The introduction of the loot methyl, 918 configuration may be the first step to be carried out as in the following.

general method:

(a) Introduction of the retro-structure into steroids of the normal series by irradiation of suitable A steroids; (b) Introduction of substituents into retro-steroids;

(c) A series of reactions to obtain a desired grouping at carbon atom 17, starting from retro-steroids with an aliphatic side chain of 6-10 carbon atoms at carbon atom 17.

The sequence of the processes as described may be varied. For example, starting from a retro-steroid which has been prepared beforehand, for example dihydroisolumisterone, the side chain degradation and introduction of the desired substituents may be carried out entirely or partially in the inverted sequence. Z-fiuoro-retro-progesterone may be prepared for example by introducing a fluorine atom in the 2-position in retro-progesterone or by side chain degradation of 2-fiuoro-dihydroisolumisterone.

It is also possible to carry out the irradiation with steroids of the normal series, in which all of the desired substituents have been introduced, or after entire or partial side chain degradation for example with lo-methyl-pregna- 5,7-diene-3B-ol-20-one.

The sequence of the processes which is chosen can be decided separately for the product and starting materials employed.

Changes in the nuclear structure other than the introduction of the 1011 methyl, 9,6 configuration may be carried out as follows:

l4fl-steroids may be prepared by hydrogenation of 14(15) unsaturated steroids, for instance with hydrogen and using palladium as a catalyst. Thus pregna-S,14,l6- trien-3fl-ol-20-one when hydrogenated yields 14p, 17ppregna-5-en-3B-ol-20-one. (Fieser and Fieser, Steroids" 1959, page 567.)

Bot-steroids may be prepared by irradiation of 17-keto steroids with ultra violet light according to Fieser and Fieser, Steroids, 1959, page 520. Thus irradiation of Sa-hydmxy-Sa-androstan-17-one yields 3a-hydroxy-5a, 13a-androstan-17-one.

8oz steroids may be prepared by hydrogenation of 11- keto-A8(9) steriods in the presence of a catalyst. (Tetrahedron 1, 22 (1957).) Thus 318-hydroxy-1l-oxo-androstfi(9)-ene may be hydrogenated in the presence of palladium to produce Elfi-hydroxy-l1-oxo-8a-androstane.

l8-nor steroids may be prepared by reacting IS-hydroxy- 17-keto steroids with sodium hydroxide (Fieser and Fieser Steroids, 1959, page 470). Thus by reacting 3B, l8-'dihydroxy-androst-S-en-17-one with sodium hydroxide will be produced 3Bhydroxy-18-nor-androst-5-erl-l7 one.

The expressions: inorganic acid, acyl, acyloxy, alkoxy, aralkoxy, acylthio, ketol'and ketalized oxo, whenever used in this application, have the following meanings.

Inorganic acid is one of the following inorganic acids: phosphoric acid, sulphuric acid, nitric acid, nitrous acid, boric acid.

Acyl or acyloxy are the acyl or the acyloxy spectively of the following acids: I

(a) Saturated 'or unsaturated, branched or unbranched, cyclic or non-cyclic aliphatic monoor dicarboxylic acids having 1-20 carbon atoms wherein the aliphatic part of the molecule may be substituted by one or more halogen atoms, amino groups, sulphonic acid groups.

(b) Phenylalkyl monoor dicarboxylic acids of which the phenyl part of the molecule may be substituted with alkyl groups containing 1-3 carbon atoms, sulphonic acid groups, alkoxy groups of which the alkyl group is branched or unbranched and contains 1-10 carbon atoms and acids of which the alkyl part of the phenyl alkyl monoor dicarboxylic acid contains from -6 carbon atoms and is branched or unbranched, saturated or unsaturated, of these acids the following specific examples may be given: formic acid, acetic acid, acroleic acid, isobutyric acid, vpalmitic acid, cyclohexan'e-mono-carboxylic acid, trichloroacetic acid, aminoacetic acid, oxalic acid, malonic acid, maleic acid, benzoic acid, terephtlialic acid, p-ethyl benzoic acid, benzene sulphonic acid, m-ethoxy benZoic acid, phenyl acetic acid, and cinnamic acid.

Alkoxy is the alkory group of mono or di-aliphatic alcohol of which the alkyl group contains from 1-20 carbon atoms and which may be branched or unbranched, cyclic or non cyclic, saturated or non saturated and which alkyl group may be substituted with halogen or alkoxy, whereby this latter alkoxy substituent may be attached to the same carbon atom of the steroid nucleus as the main alkoxy group. Of these alcohols the following examples may be given: methanol, ethanol, propahol-2, 2-chloro ethanol-1, 2-ethoxy ethanol- 1 and glycol.

Aralkoxy is the aralkoxy group of a mixed aromatic aliphatic alcohol in which the hydroxyl group is attached to the aliphatic part of the molecule and of which the alkyl(ene) group contains from 06 carbon atoms which may be branched or unbranch'ed. Of these alcohols the following examples may be given: benzyl alcohol and phenol.

Acylthio is the acylthio group of acyl thiols. In acylthio the expression acyl has the meaning as given hereabove.

A ketal is the dihydroxy steroid ketal of an aliphatic aldehyde, aliphatic ketone, mixed aliphatic aromatic aldehyde, mixed aliphatic aromatic ketone, or a diaromatic ketone.

Ketalized oxo is the ketalized oxo group resulting from the reaction between two molecules of a m'onohydroxy aliphatic alcohol containing from 1 to 6 carbon atoms and one molecule of an oxo group containing 100:, 9c methyl steroid, or resulting from the reaction between one molecule of a diliydroxy aliphatic alcohol containing from 1 to 6 carbon atoms and one molecule of an axe group containing 10oz, methyl, 9,8 steroid.

The introduction of alkyl substituents may be carried out as follows:

-(1) By the reaction of keto-, conjugate ketoand doubly conjugate keto-steroids with alkylation agents, such as, for example, Grignard reagents, alkyl-alkali-metal compounds or an alkyl halide, in the presence of an alkali metal alkoxide.

For example, according to the method described by Zderic et al. (I. Am. Chem. Soc,, 82, 3404 (1960)) l1- keto-retno steroids lithium give the corresponding ll-mcthyl-li-hydroxy steroids. In this manner, ll-keto-retroprogesterone 3,20-bisethylene ketal may be converted to groups re- 1 the corresponding -11-methyl-1l-hydroxy compound. After acid hydrolysis, this provides ll-methyl-l l-hydroxy compound. After acid hydroylsis, this provides ll-methyl-l 1 hydroxy-retro-progesterone.

Further, ll-keto-retro-testosterone I i-ethylene ketal may be converted into the corresponding ll-meth'yl-l l-hydroxy compound. After acid hydrolysis, this yields the ll-methyl-l1-hydroxy-retro testosterone.

The reaction of 6-keto-retro-st-eroids with methyl magnesium halides gives the 6-methyl 6-hydroxy steroids, for example by the method described by Fieser et al. (J. Arn. Chem. Soc. 73, 4660 (1951)). In this manner, 6-keto retro-pregnane-3-ol-20-one 20-ethylene ketalv may be converted into 6-m'eth'yl-ii,6-dihydroxy-retro-pregnane- 20-one 20-ethylene ketal.

Further, 6-keto-retro-androstane-3,17 diol may be converted into 3,6,'17-trihydroxy-6 methyl-retro-androstane. The reaction of 3-keto-retro steroids with methyliodide in the presence of potassium-t-butoxide by the procedure of Ringold et al.: (J. Am. Chem, Soc, 81, 427 (1959)) providcs the corresponding 2,2-dim'ethyl steroids. In this manner, 2,Z-dimethyI-retrQ-pregnane-S,ZO-dione 20-ethylene ketal may be produced from retropregnane-3,20- dione 20-ethylene ketal.

Further, 2,2-dimethyl retro androstane 17,8-ol-3-one may be produced from retro-androstane-l7fl ol-3-one may be produced from r'etro-androstane-i7l3-ol-3-one.

Addition of methyl Grignard reagents to A -20-ketoretro pregnanes according to the method described by Bernstein et al. (J. Org. Chem., 26, 269 (1961)) provides 16-methyl compounds. Thus 3B-hydroxy-l6-methyl-retro-pregn-S-erie-ZO-one may be produced from 35- acetoxy-retro-pregna-5,16 diene-2O-one.

Conversion of S-keto-M-retro-steroids with methyl halides in the presence of potassium-t-butoxide bythe procedure of Woodward et al. (I. Am; Chem. Soc. 76, 2852 (1954)) gives 3-keto-4,4 d imethyl-A steroids. For example, such a reaction with bismethylene-dioxy-retrohydrocortisone gives the 4,4-dimethyl-17(20),20-bismethylenedioxy-retro-pregn-5-ene-3,20-dione.

Further, with retro-testosterone, such a reaction gives the 4,4-dimethyl-retro-androst-S-ene-l7fi-ol-3-one.

(2) By the addition of diazomethane to double bonds, succeeded by pyrolysis or cleavage under acid conditions of the pyrazolines, if required with subsequent hydrogenation of the compounds obtained. According to the procedure of Weichert and Kaspar (Chem. B-er., 93, 17 10 1960)) A -3-keto-retro-steroids react with diazometham with the formation of pyraz'oli'nes, from which the 1,2-methylene-n -3drew-steroids are produced by pyrolysis. Under the action of, for example, acid alumina, however, the pyrazolines are converted into the A -lmethyl steroids. For example, l7a acetoxy-.l,2 methyl ene-rctro pregna-4,6-diene-3, 20-dione and '17a-acetoxy-1- methyl-r'etro-pregna-l,4,6-triene-3,20-dione may be produced from 17ot-acctoxy-retro-prcgna 1,4,6-triene-3,20- dione. Further, l,2-methylene-retro-androsta-4,6-dicne-1719-01- 3-one l7-acctate and l-methyl-retro-androsta-1,4,6-trine 17fl-ol-3-one 17-acetate'may be produced from retroandrosta-l,4,6-triene-1718-ol-3-one 17-acetate.

(3) By the reaction of a methylene group activated by a keto-group, with a inonoor dicarboxylic acid ester o (It-iJ-O-alkyl where R may be H or succeeded by a reaction with an alkyl halide with subsequent splitting off of the carboxylic acid group.

For example, 3-keto-A -retro-steroids when reacted with diethyloxalate in the presence of sodium hydride according to the method described by Ringold et al. (J. Am. Chem. Soc. 81, 427 (1959)), after reaction with a methyl halide followed by a reaction with an alkalialkoxide give the Z-methyl-3-keto-A -retro-steroids. Thus, from retro-pregn-4-ene-20-ol-3-one 20 acetate the 2- methyl-retro-pregnt-ene-20-ol-3-one ZO-acetate may be produced.

Further, in this manner Z-methyl-retro-testosterone may be produced from retro-testosterone.

(4) By the reaction of retro-steroid epoxides with,

for example, aIkyl Grignard reagents. For example, 3- cycloethylenedioxy-5(6)-epoxy-retro-steroids after reaction with methyl magnesium halides according to the method described by Babcock et al. (J. Am. Chem. Soc., 80, 2904 (1958)) give the 6-methyl-5-hydroxy compounds, from which after hydrolysis and dehydration the 6-methyl-3-keto-A -retro-steroids can be produced. Such a reaction with, for example, 5,6-epoxy-l7a-hydroxyretro-pregnane-3,20-dione bisethylene acetal gives the corresponding 5-hydroxy-6-methyl compound which, after hydrolysis and subsequent dehydration, provides the. 6- methyl-17m-hydroxy-retro-progesterone.

Further, -from 5,6-epoxy-retro-androstane3,17-diol may be obtained in this manner 5-hydroxy-6-methyl-retroandrostane-3,17-diol.

The introduction of double bonds in retro-steroids may be effected by the following methods:

(1) By microbiological dehydrogenation, as described, for example, for the production of l-dehydro-steroids by Sih et al. (J. Am. Chem. Soc., 82, 2653 (1960)). In this manner, retro-progesterone may be converted into 1-dehydro-retro-progesterone, or, retro-testosterone may be converted into 1-dehydro-retro-testosterone.

(2) By the direct dehydrogenation of saturated or nonsaturated steroid ketones and of unsaturated steroids with, for example, mercury acetate, iodine pentoxide, selenium dioxide, manganese dioxide, substituted quinones such as chloranil and dichlorodicyanobenzoquinone, for example by the methods of Heilbron et al. (J. Chef. Soc., 1935, 1221), Burn et al. (Proc. Chem. Soc. 1960, 14), Agnello et al. (J. Am. Chem. Soc., 82, 4293 (1960)) and Sondheimer et al. (J. Am. Chem. Soc., 75, 5932 (1953)). In this manner, 6-dehydro-retro-progesterone may be produced from retro-progesterone and 1,6-bisdehydro-17aacetoxy-retro-progesterone may be produced from 6-dehydro-17a-acetoxy-retro-progesterone. 3,17-diacetoxy-retroandrosta-5,7,9(11)-triene may be obtained from 3,17-diacetoxy-retro-androsta-5,7diene, and l-dehydro-retrotestosterone may be obtained from retro-testosterone.

(3) By the splitting off of substituents, for example dehydrohalogenation of halogenated retro-steroids, for example with an organic base, as has been described by Djerassi et al. (J. Am. Chem. Soc., 72, 4534 (1950)) for the production of 6-dehydrofrom 6-halo steroids. In this manner, 6-dehydro-retro-p-rogesterone may be produced from 6-bromo-retro-progesterone. Further, 6-dehydro-retro-testosterone 17-acetate may bev produced from 6-bromo-retro-testosterone 17-acetate.

Another example of splitting of? is the dehydration of hydroxylated retro-steroids, for example under the influence of phosphorus-oxychloride and an organic base, from methane sulphonyl chloride or from methyl chlorosulphite, for example by the methods described by Chamberlin et al. (J. Org. Chem. 25, 295 (1960)). In this manner, retro-hydrocortisone acetate may be converted into 1711,21 dihydroxy-retro-pregna-4,9(11)-diene-3,20-dione 21-acetate. Further, 1l-hydroxy-retro-androst-4-ene-3,20- dione may be converted into retro-androsta-4,9(1l)-diene-3,20-dione.

The introduction of hydroxy groups into retro-steroids may be eflfected as follows:

(1) By microbiological hydroxylation, for example as described by Peterson et al. (J. Am. Chem. Soc., 74, 1871 28 (1952)). In this manner, 11,l7u,2l-trihydroxy-rctropregn-4-ene-3,20-dione may be produced by microbiological hydroxylation of I7a,21-dihydroxy-retro-pregn-4-ene- 3,20-dione. Further, l1-hydroxy-retro-testosterone may be produced by microbiological hydroxylation of retrotestosterone according to the same method.

(2) By cleavage of epoxy-retro-steroids. This may be effected by means of reducing agents, such as, for example alkali-bariumand alkali-aluminum-hydride, chromium salts, and by catalytic hydration. According to the method described by Cole et al. (J. Org. Chem., 19, 131 (1954)), the 16 hydroxy compounds may be produced from 16,17-epoxy-retro-steroids. Thus, 16,17-epoxy-retropregn-4-ene-21-ol-3,20-dione yields the retro-pregn-4-ene- 16,21 -diol-3,20-dione. Further 3,17-dihydroxy-5(6)- epoxy-retro-androstane may be converted into 3,6,17-trihydroxy-retro-androstane.

Cleavage of epoxy-retro-steroids may also be performed by means of hydro halogenic acids, for example as described by Ringold et al. (J. Am. Chem. Soc., 78, 816 (1956)) for the production of 17a-hydroxy-pregnanes from 16,-17-epoxy-pregnanes. According to this method, 16,17-epoxy-retro-progesterone, after reaction with hydrogen bromide succeeded by reductive debromination, yields the 17a-hydroxy retro progesterone. Further, 9(l1)-epoxy-retro-androst-4-ene-17B-o1-3-one with hydrogen fiuoride yields 11-hydroxy-9-fiuoro-retro-tcstosterone.

(3) By hydroxylation of double bonds, for example with osmium tetroxide. For example, osmate esters, produced by oxidation of alkenes with osmium tetroxide, are split up into the diols, employing the'procedure of Baran (J. Org. Chem., 25, 257 (1960)). In this manner, 3- hydroxy-retro-pregn-5-ene-20-one may be converted into 3,5,6-trihydroxy-retro-pregnane-ZO-one. Further, 3B-hydroxy-retro-androst-S-ene-17-one may be converted into 318,5,6-trihydroxy-retro-androstane-17-one.

(4) By the reaction of enol ethers or enol esters with organic peracids. If, for example, A -3-enol acylates are reacted with per-acids, employing the methods of Romo et al. (J. Org. Chem., 19, 1509 (1954)), the 3-keto-A -6- hydroxy steroids are produced. Thus, 3-acetoxy-retropregna-3,5-'diene-20-one with monoperphthalic acid yields the 6-hydroxy retro-progestcrone. Further, 3,17,8-diacetoxy-retro-androsta-3,5-diene with monoperphthalic acid yields the 6-dehydro-retro-testosterone l7-acetate.

(5) By the hydrolysis or acyloysis of halo-steroids, for example with an alkali salt of a carboxylic acid by the method of Ruschig (Ber., 88, 878 (1955)), 21-iod0- steroids being converted with potassium acetate into the 21-acetoxy compounds. Hydrolysis of these compounds, for example according to Robinson (J. Am. Chem. Soc., 82, 4611 (1960)) with perchloric acid yields the free 21- hydroxy compounds. The hydrolyses may suitably be performed with a solution of potassium bicarbonate in aqueous methanol. Thus, 21-iodo-retro-progestcrone may be converted into 21-acet0xy-retro-progesterone, which again may be converted by hydrolysis into 21-hydroxyretro-progesterone. Further, in this reaction 6-bromoretro-testostcrone 17-acetate gives 2-1celoxy-retro-testosterone l7-acetate, from which, after hydrolysis, 2-hydroxy-retro-testosterone is obtained.

(6) By reduction of keto-steroids, for example with lithium aluminum hydride by the method described by Sondheimer et al. (J. Am. Chem. Soc., 75, 5930, 5932 (1953)). In this manner. retro-progesterone may be reduced to rctro-pregnl-cne-diol. Further. for example, retro-androst-4-ene-3.l7-dione may be reduced to retroandrost-4-ene-3, l 7-diol.

(7) By hydrolysis of esters or ethers, for example by the method of Dory ct al. (C.A., 53, 17181 (1955)) with sodium methylate in methanol. The saponification may also be performed with dilute inorganic acids, dilute inorganic bases, sodium carbonate and sodium bicarbonate. Thus, hydrolysis of 17a,2l-dihydroxy-rctro-progesterone 21-acetate with sodium bicarbonate in dilute dioxane gives the 170:,21-dihydroxy-retro-progesterone.

Further, the hydrolysis of retro-testosterone 17-acetate gives retrotestosterone.

The introduction of acyloxy groups into the retrosteroid series may be carried outasfollows:

(1) By acyloysis of halo-retro-steroids as described hereinbefore.

(2) By the reaction of hydroxyan'd keto-retrosteroids with acids, acid anhydrides or acid chlorides in" the presence of, for example, a catalyst (for example, ptolueue' sulphonic acid, pyridine-HCI) or acid binding reagents (for example organic bases) or water-binding reagents (such as, for example, trifluoro acetic acid anhydride). For example, 17a-ethyl-retrotestosterone may be esterified with the acid chloride of B-phenyl-propionate in pyridine by the method of Gould et al. (J Am. Chem. Soc., 79, 4472 (1957)) to form 17-(B-phenyl-propionate) ester of l7a-ethyl-retro-testosterone. Further, retroandrost-4-ene-17fl-ol-3-one l7-(fl-phenyl propionate) may be obtained by esterification of retro-testosterone with the acid chloride of fi-phenyl propionic acid in pyridine.

The introduction of alkoxy and aralkoxy groups into the loot methyl 913 steroid series may be carried out, as follows:

(1) By the reaction of keto-retro-steroids with a suitable hydroxy compound (mono or' poly), for example, in the presence of a catalyst, such as, for example, hydrochloric acid, pyridine-hydrochloric acid and p-toluene sulphonic acid, employing the method described by Ercoli et al. (J. Am. Chem. Soc., 82, 746 (1960) In this manner, the cyclopentyl enolether of 17a-acetoxy-retro-progesterone may be produced. Another example is the production of the 3-enol benzyl ether of 6-dehydro-retroprogesterone by the action of benzyl alcohol and hydrochloric acid on 6-dehydro-retro-progesterone. Further, the cyclopentyl enol'ethcr of retro-testosterone may be produced in this manner from retro-testosterone and cyclopentanol.

(2) By an acid-catalysed interchange reaction between the chosen hydroxy compound and preformed enol ether, for example by the method of Ercoli et al. (J. Am. Chem. Soc. 82, 746 (1960) In this manner, 3-enol ethyl ether of retro-progesterone may be converted into 3-enol benzyl ether, or, 3-enol ethyl ether of retrotestosterone may be converted into 3-enol benzyl ether.

(3) By the reaction of keto-retro-steroids with trialkyl orthoformates with the use of an acid catalyst, for exam ple, an ethanolic hydrogen chloride solution, for example by the method of Ruyle et al. (J. Org. Chem., 25, 1260 (1960) In this manner, 17e-[2-methallyl]-retro-testosterone may be converted into 3-ethoxy-l7a-[2 methallyl]-retro-'androsta3,5-diene l76-01, or retro-testosterone may be converted into 3-ethoxy-retro-androsta-3,S-diene. 17fl-ol.

(4) By the reaction of a hydrox y-retro-steroid with an alcohol in the presence of a catalyst, such as, for example, an inorganic acid or p-toluene sulphonic acid, for example by the method of Sondheimer et 'al. (Tetrahedron, 5, (1959)). In this manner, 3-methoxy-retro-pregn-4- ene-20-one may be produced from 3-hydroxy-retro-pregn- 4-ene-20-one, 3-methoxy-retro-androst-4-ene-175-01 from 3,173 dihydroxy-retro-androst-4-ene, 3-methoxy-retropregn-4-ene-20-one from 3-hydroxy-retro pregn-4-ene-20- .one, and 3 -methoxy-retro-androst-4-ene-175-01 from 3,175-dihydroxy-retro-androst-4-ene.

(5) By the reaction of a hydroxy-retro-steroid with diazomethane in the presence of a catalytic amount of fluoboric acid by the method of Neeman et a1. (Tetrahedron, 6, 36 (1959)). Thus, 3-methoxy-retro-pregn-4-ene-20- one is obtained from retro-pregn-4-ene-3-ol-20-one. Further, 3-hydroxy-retro-androst-4-ene-17-one may be converted into 3-methoxy-retro-androst-4-ene17-one.

The production of halo-retro-steroids may be carried out as follows:

(1) By the addition of halogen to double bonds in retro-steroids, for. example by addition of chlorine to 3- hydroxy-M-retro-steroids or addition of mixed halogens, such. as BrF- and IF, to A -retrosteroids according to Bowers et al. (J. Am. Chem. Soc., 82, 4001 (1960)). By this method, 171:,2l dihydroxy-retro-pregna-,4, 9(11)-diene 3,20-dione al-acet-ate may be converted into the 9,1ldihalo compounds. Thus, for example, 9(11)-dehydroretro-testosterone may be converted into 9,1l-dihalo-retro-testosterone.

.'(2) By.- the substitution-halogenation at an allyl position-adjacent to a double bond or of a methylene group adjacent to a keto group in retro-steroid s, for example with bromine, N-bromo-succinimide, dibromo-dimethylhydantoin etc., for example by the method of- Djerassi et a1. (J; Am. Chem. Soc., 72', 4534 (1950)) for the production of 6fhalo-3-keto-At steroids from 3-keto-A steroids. Thus, retro-progesterone ZO-cycIo-ethylene ketal may be brominated to form the G-bromo compound and retro-testosterone 17-acetate may be converted into 6- bromo retro testosterone 17' acetate. Furthermore, retro-pregmS-ene-3fl-ol-20 one 3-acetate may be converted into 17m-bromo-retrorpregn-5-ene-3;8-o1-20-one 3-acetate, the double bond being. protected during the reaction by conversion of the dibromide by the method of Engel et al. (Can. J. Biochem. PhysioL, 35', 1047 (1957) and Can. J. Chem., 38, 452 (1960) (3) By the reaction ofenol esters, enol ethers and enamines with halogenating agents, suchas, for example, halogen, N-halo-imides, perchloryl-fluoride, BrF. In this manner, 3-enol esters of 3-keto-A -retro-steroids may be converted with perchlorylfluoride according to the method of Bloom et al. (Chem. a. Ind., 1959, 1317) into the 3eketo-M-fi-fiuoro-retro-steroids. By this method, the 3-enol acetate of retroprogesterone may be converted into 60:.- and 6fl-fluoro-retro-progesterone, and, 3 -enol acetate of retro-testosterone 17-acetate may be converted into 6ocand Gfl-fiuoro-retrodestosterone 17-acetate.

Furthermore, the 3 enol ethers of 3-keto-A -retrosteroids may be converted with N-halo-imides by the method of Ringold et al. (J. Am. Chem. Soc., 81, 3485 (1959)) into the 6-halo-3-keto-A -retrosteroids. Thus, reaction of 3-ethyl enol ether of l7a-acetoxy-retroprogesterone with N-chlorosuccinimide gives 6-chlorol711-acetoxy-retro-progesterone. Further, reaction of 3-enol ethyl ether of retro-androst-4-ene-3,l7-dione with N-chlorosuccinimide yields 6-chloro-retro-androst-4-ene: 3,17-dione.

Furthermore, the enamines of 3-keto-A -rctro steroid may be converted by a reaction with perchlorylfiuoride followed by isomerisation with, for example, hydrochloric acid by the method of Joly et a1. (Bull, 1961, 569) into 3-keto-4-fiuoro-a' -retro-steroids. Thus, the 3-pyrrolidyl- A -enamine of 17a-acetoxy-retro-progesterone yields the 4-fluoro-l7a-acetoxy-retro-progesterone, and 3-pyrrolidyl- AW-enamine of retro-testosterone yields 4-fiuoro-retrotestosterone.

(4) By the reaction'of retro-steroids of the following type: retro-steroid I where R is an alkyl group and R may be H or Jim-R. where R; may be an alkyl group, which may be obtained by condensation of a methylene group ll. ll

activated by a keto-group with a monoor dicarboxylic acid ester (for example ethylformate, diethyloxalate), with halogenating agents, such as halogen and perchlorylfluoride, with subsequent splitting off of the carboxylic 31 acid group. Thus, according to the method of Kissman et al. (J. Am. Chem. Soc., 82, 2316 (1960)), the sodium salt of 21-ethoxallyl-retro-progesterone may be converted with perchloryl-fiuoride and subsequent treatment with potassium acetate into 21-fluoro-retro-progesterone. Substitution of bromine for the perchlorylfiuoride gives 2l-bromo-retro-progesterone. Further, according to the method of Edwards et al. (I. Am. Chem. Soc., 81, 5262 (1960)) Z-fluoro-retro-testosterone may be produced from the sodium salt of 2-hydroxymethylene-retro-testosterone by reaction with perchlorylfluoride and subsequent treatment with potassium acetate.

By cleavage of epoxides, for example with hydrohalogenic acids or BF for example by the method of Romo et al. (J. Org. Chem., 21, 902 (1956)), according to which 16(17)-epoxides are treated with HBr. Thus, 16(17)-epoxy-retro-progesterone may be converted into l6-bromo-l7u-hydroxy-retro-progesterone. According to the method of Bowers et al. (Tetrahedron, 3, 14 (1958)), 6-fiuoro-3,17-diacetoxy-retro-androstane-S-ol may be produced from 3,17-diacetoxy-5(6)-epoxy-retro-androstane.

The introduction of oxo-groups in retro-steroids may be carried out as follows:

(1) By oxidation of hydroxy-retro-steroids, for example according to Oppenauer as described for the normal series by Shepherd et al. (I. Am. Chem. Soc., 77, 1212 (1955) By this method, retro-pregn-S-ene-3-ol-20- one maybe converted into retro-progesterone, or retroandrost-5-ene-3-ol-17-one may be converted into retroandrost-4-ene-3,l7-dione. The oxidation may also be performed with chromic acid, for example, in pyridine, by the method of Sondheimer et al. (Tetrahedron, 5, 15 1959)). Thus, 20-hydroxy-retro-pregn-4-ene-3-one may be converted into retro-progesterone. Further, from retro-testosterone will be obtained androst-4-ene-3,17- dione. The oxidation of hydroxy-groups occupying an allyl position with respect to a double bond, may suitably be performed with manganese dioxide, for example by the method of Sondheimer et al. (J. Am. Chem. Soc., 75, 5930 (1953)) and with quinones, such as, for example, dichloro-dicyanobenzoquinone as described by Burn et al. (Tetrahedron Letters, 9, 14 (1960)). Thus, retro-pregn-4-ene-3,20-diol may be converted into ZO-hydroxy-retro-pregn-4-ene-3-one, and according to these two manners, retro-androst-4-ene-3,17B-diol may be converted into retro-testosterone.

(2) By oxidation of A double bonds for example by ozonisation with the formation of 17-ketones, employing the method of Pederson et al. (I. Am. Chem. Soc., 79, 115 (1957)). Thus, ozonisation of the 22-cyanohydrin of retro-bisnorchola-4,17(20)-diene-3-one- 22-al gives the retro-androst-4-ene-3,17dione.

(3) By hydrolysis of enol esters or enol ethers of retro-steroids, for example, by acid hydrolysis as described by Serini et al. (Ben, 71, 1766 (1938)). Thus, S-ethoxyretro-pregn-3,5-diene-20-one may be hydrolysed to retroprogesterone. Further, 3-ethoxy-retro-androsta-3,S-diene- 17-one may be hydrolysed to retro-androst-4-ene-3,17- dione.

(4) By the microbiological oxidation of hydroxy-retrosteroids, for example as described by Perlman (Science, 115, 529 (1952)). Thus, retro-pregn-4-ene-3-ol-20-one may be converted into retro-progesterone, or 17-acetoxyretro-androst-5-ene-3-ol may be converted into retrotestosterone 17-acetate. The production of acylthio-retrosteroids may be effected by the method of Dodson et a]. (J. Am. Chem. Soc., 81, 1224 (1959)), for example, for the introduction of 1- and 7-acylthio groups. Thus, 6-dehydro-retro-progesterone after reaction with ethanethiolic acid gives 7-acetylthio-retro-progesterone. Further, 6-dehydro-retro-testosterone after reaction with ethanethiolic acid yields the 7-acety1thio-retro-testosterone.

The production of amino-retro-steroid's may be effected by reduction of retrosteroidoximes, for example, with 32 LiAlH as described by Shoppee et al. (J. Chem. Soc., 1956, 1649). Thus, the dioxime of 6-dehydro-retroprogesterone yields 3,20-diamino-retro-pregna 4,6 diene. Further, the oxime of retro-testosterone with LiAlH, in ether yields the 3-amino-retro-androst-4-ene17,6-ol.

The production of monoalkyland dialkyl substituted amino IOa-methyl, 9fl-steroids may be effected by reacting aminoor monoalkyl substituted amino IOa-methyl, steroids with alkyl halides, for example with an alltyl bromide. Thus 3-amino-retro-androstan-1713-01 when reacted with methyl bromide yields 3-(N-methylamino)- retro-androstan-Ufi-ol.

The production of retro-steroid [2,3-d] isoxazoles may be performed by the method of Clinton at al. (J. Org. Chem., 26, 279 (1961)), by reacting 3-keto-2-hydroxymethylene retro-steroids with hydroxylamine hydrochloride. Thus, Z-hydroxymethylene-17e-allyl-retro-testosterone may be converted into 17-hydroxy-l7a-allyl-retroandrost-4-eno [2,3-d] isoxazole. Further, Z-hydroxymethylene-retro-testosterone may be converted into 175- hydroxy-retroandrost-4-eno [2,3-d] isoxazole.

The production of retro-steroid [3,2-c] Pyrazoles may be performed by the method of Clinton et al.(J. Am. Chem. Soc., 81, 1513 (1959)) by reacting 3-keto-2-hydroxymethylene retro-steroids with hydrazine. Thus, 2- hydroxymethylene-retro-pregn-4-ene-20-01-3-one by reaction with hydrazine yields 20-hydroxy-retro-pregn-4-eno [3,2-c] pyrazole. Further, reaction of 2-hydroxymethylene-6-dehydro-retro-testosterone with hydrazine gives 176- hydroxy-retro-androsta-4,6-dieno [3,2-c] pyrazole.

The preparation of oxide 10a-methyl-9p steroids can be performed by reacting a double bond between the carbon atoms under consideration with an oxidizing agent such as hydrogen peroxide in the presence of an alkali or with an organic peracid such as monoperphthalic acid. Thus 6-dehydro'retro-progesterone when reacted with monoperphthalic acid yields 6,7-oxido-retro-progesterone.

The introduction of methylene groups into wot-methyl 9,6 steroids may be effected by the addition of diazomethane to the double bond present in such a steroid and cleavage of the thus obtained pyrazolines according to the procedure of Wiechert and Kaspar (Chem. Ber., 93, 1810 1960)). Thus 16-dehydro-retro-progesterone may be converted into 16-methylene-retro-progesterone.

The introduction of thiol groups (-SH) into methyl 95 steroids may be effected as follows: The reaction of a steroidtosylate with thiourea and splitting of the thus formed isothiouronium compound with alkali hydroxide atfords the desired thiol 10a methyl 9 steroid. Thus 3- thiolo-androst-4-en-17fi-ol 17-acetate can be prepared from 3-tosyloxy-androst-4-en-17,9-01 17-acetate.

The introduction of the thio analogues of alkoxy and aralltoxy groups into 1011 methyl 96 steroids can be effected by reacting an OXO-lOa methyl, 9 8-steroid with an alkyl thiol or an aralkyl thiol respectively in the presence of a catalyst such as p-toluene sulphonic acid. retro-testosterone when reacted with ethyl mercaptane yields 3-enol ethyl thio ether and when reacted with benzylmercaptane yields 3-enol benzylthioether of retro-testosterone.

The preparation of 2'-methyl-(3,2-d)-thiazoles may be carried out according to the process described by Doorenbos et al. (J. Pharm. Sc., 50, 271 (1961)) by reacting 2- bromo-3-keto retro-steroids with thiacetamide. Thus 2- bromo17a-methyl-retro-testosterone may be converted into 2'-methyl-(3,2-d)-thiazolo-17a-methyl-retro-androsta- 2,4-dien-17-ol.

The synthesis of 2'-amino-(3,2-d)-pyrimidino retrosteroids may conveniently be performed by the reaction of 2-hydroxy methylene-3-keto-rctro-steroids with guanidine according to the process described in Bull. Off. de la Trop. Ind., 1, 344 (1961). Thus 2'-amino-(3,2-d)-pyrimidino-retro-androsta-4,6-dien--01 17-acetate can be prepared from 2-hydroxyymethylene-6-dehydro-retro-testosterone 1 7-ac etate.

Thus

The production of 6-nitro retro-steroids may be etfected by nitration of 3,5-dienylacylates of retro-steroids as described by Bowers et al. (J. Am. Chem. Soc., 81, 3707 (1959)). Thus, 3,l7a-diacetoXy-retro-pregna-3,5-dien-20- one can be converted into 6-nitro-l7a-acetoxy-retro-progesterone.

The introduction of an oxygen atom in the l8-methyl group in retro-steroids can for instance be carried out by the irradiation of a ll-nitrite of 1l-hydroxy-retro-steroids according to the process described by Barton et al. (J. Am. Chem. Soc., 82, 2641 (1960)). Thus retro-corticosterone 2l-acetate can be esterified into the corresponding ll-nitrite. Irradiation of this compound in toluene yields the retro-aldosterone 21-acetate oxime, which can be transformed by the action of sodium nitrite in acetic acid into retro-aldosterone ZI-acetate.

Retro-l7-spirolactones may be prepared by reaction of a 'l7macetylenic substituted retro-steroid with an alkyl gregnard halide, decomposing the complex thus formed with carbon dioxide and after hydrogenation lactonizing the thus formed hydroxy-acid, as described by Cella et al. (J. Org. Chem., 24, 743 (1959)). Thus 17a-ethinyl-3,17- dihydroxy-r'etro-andrbst-S-ene is converted into 3,17-dihydroxy-retro-androst-S-en-17a ylpropynoic acid, after which catalytic hydf-ogenation yield 3'-(3,17-dihydroxyretro-androst-S-en-l7kx-yl) propenoic acid lactone. Repeated hydrogenation gives the corresponding l7-propanoic lactone, which by means of an Oppenauer-oxidation can be converted into the 3-keto-A -retrospirolactone.

Trihalo methylretro-steroids can be prepared by the reaction of enol ethers of unsaturated ketones with tetrahalo methanes as described by Lusberg et a1. (Tetrahedron, 9, 149 (1960)). Thus the reaction of the A- enolethyl ether of retro-progesterone with tetrabro'mo methane yields 6-trib'romomethyl-retro-progesterone. In the same manner the trifluoroand trichloro compounds may be prepared. The latter compound can by splitting off HBr and/ or reduction be converted in 6-methyl-retroprogesterone.

The methods of preparing the novel retro steroids of our invention will now be explained in greater detail in the examples which follow.

Example 1 (a) By very vigorous stirring, 125 g. of A4,7,22-lumistatrien-3-one were dissolved at 10 C. in 2.2 litres of dry propanol-Z, which had previously been saturated with dry hydrochloric acid gas. The hydrochloric acid gas was slowly passed through the liquid for an additional half hour. The liquid was then decanted as rapidly as possible, while stirring, into a mixture of solid sodium bicarbonate and a saturated bicarbonate solution, obtained by stirring 4 kg. of sodium bicarbonate with 8 litres of water. After a short period of time the yellowish propanol-Z layer was separated out and the salt layer extracted twice with one litre of petroleum ether. The combined layers were then washed three times with a sodium bicarbonate solution and water, then dried on sodium sulphate and evaporated to dryness after filtering. The ultraviolet absorption spectrum exhibited a maximum at 287 mg, of which the 1 En... is 562 (content of pure substance about 85%).

The residue obtained was dissolved in 250 ml. of boiling petroleum ether (40 to 60 C.) and crystallized at C. for a few hours and finally overnight at --25 C. Filtering yielded 80.5 g. of lumista-4,6,22-trien-3-one with a melting point of 99 to 100.5 C. (yield 64%). A por- :tion of the last substance was recrystallized a few times with petroleum ether for analysis, the melting point rising to l0ll02 C. The further analytical values were: [a] =-632 (CHCI s(7\=287 m .)=26,200.

Found: C, 85.67%, 85.68%;1-1, 10.65%, 10.77%. Calculated for C H O: C, 85.22%; H, 10.73%. In the 34 infrared spectrum there were found apart from the 964 cm. band for the side chain trans-ethylene bond three characteristic bands at 1586, 1622 and 1661 cmr (b) While stirring vigorously, a solution of 3.0 g. of

- lumista-4,6,22-trien-3-one in 300 ml. of dry diethylether was added to 450 ml. of liquid ammonia. During the addition of the first portion of the solution crystallization occurred but the soliddissolved after a larger portion had been added. Then, while stirring vigorously, a solution of 420 mg. of lithium in 100 ml. of ammonia was care fully added in drops, until no spontaneous decoloring occurred any more. ml. of dry ethanol were then added dropwise,'stirring was continued for 30 minutes, the mixture was diluted with water and the reduction prodnot was dissolved in diethyl ether. The ethereal extracts were then extensively washed with water, dried on Na SO, filtered and evaporated to dryness yielding a light-yellow resin.

(Elam, (r max. 242 m )=19e) The resin was dissolved in ml. of boiling ethanol and after the addition of 6 ml. of 2 N NaOH the solution was boiled for five minutes. The solution was then rapidly cooled. By diluting with water, absorbing in diethyl ether, washing of the ethereal layers with water, drying, filtering and evaporating to dryness, a light-brown residue was finally obtained with E1? (A max. 242 m l) 420 This substance was chromatogra'ph'ed in 25 ml. of pure benzene on 30 g. of Al 0 (IH) and eluated with the same solvent (total 75 ml.), a dark brown ring remaining at the upper end of the column. The dry eluate was recrystallized with 45 ml. of methanol at 5 C., after which the filtered product was washed with 20 ml. of methanol of 25 C. The yield were long light-brown needles (1.5 to 2 ems. in length), weight 2.43 g. and melting point 122 to 124 C.

500 mg. of this substance were recrystallized twice with 3 ml. of acetone at 5 C., after which finally 313 mg. of colorless crystals of lumista-4, 22-dien-3-one were obtained.

The analytic values found for this pure substance were:

0242 m )=16,800 melting point 122-124 C.

MD: --l25 (01101 Found: C, 84.98%, 84.89%; H, 10.96%, 11.03%. Calculated for C I-I 0: C, 84.79%; H, 11.17%.

In the infrared spectrum an intense band was found at 1665 cm." a slightly weaker band at 1620 cm.- a weak band at 962 cm.- and a slightly more intens band at 978 cr'nf 20 g. of lumista-4, 22-dien-3-one was dissolved in a mixture of 750 ml. of freshly distilled methylene chloride and 5.75 ml. of dry pyridine. The mixture, while being stirred magnetically at 80 C. (carbon dioxide ice and acetone) for 4 and /2 hours was ozonised (0.205 mol ozone per min), speed of passing oxygen (V )=9 to'10 l./hour. The ozonide formed was then decomposed at 0 C. for one hour by stirring it with a suspension of 20 got zinc powder, after the addition of ml. of glacial acetic acid. The reaction mixture was then warmed for 5 minutes at 35 C., and then the resultant solid substance was separated out by filtering. After the addition of ice the filtrate was washed successively with 75 ml. and 50 ml. of ice cold 10% bla CO solution, three times with 50 ml. of 10% Nafiii solution at 0 C. and four times with 300 ml. of ice water.

The methylene chloride layer was then dried on Na SO filtered and the filtrate was distilled to dryness, the last part of which was carried out in vacuo. The colorless, practically completely crystalline residue was recrystallized with 50 ml. of diethylether at 25 C., the first crystallate being 10.1 g. of 3-keto-retro-bisnor- :(Amax 242.5 ma=16,700, [a] =144 c. circa Found: c, 79.87%, 80.06%; H, 9.73%, 9.81%. Calculated for C H O C, 80.42%; H, 9.82%.

The infrared spectrum showed characteristic bands at 1712, 1642 and 1610 cmr (c) A solution of 450 mg. of 3-keto-retro-bisnorchol- 4-en-22-al obtained as described in Example 1b in 15 ml. of chloroform and 25 ml. of acetic acid, in which 200 mg. of chromic acid and 0.2 ml. of water had been dissolved was oxidized at about 30 C. for 16 hours.

After the excess quantity of chromic acid had been decomposed by stirring for 30 minutes with 1.5 ml. of methanol, the mixture was diluted with water and the substance was dissolved in benzene. The benzene extract was washed with water to neutral reaction, dried on Na SO and filtered. After evaporation to dryness a crystalline residue was obtained, which by crystallization with diethylether, yielded 340 mg. of 3-keto-retrobisnor-chol-4-enic acid, melting point 194 to 198 C. A few crystallizations raised the melting point of this substance to 202 to 204 C.

The further analytic values found for this pure substance were:

e(7\max:242 ma):16,800.

Calculated for 11 0 C, 76.70%; H, 9.36%. Found: C, 76.93%, 76.92%; H, 9.45%, 9.48%.

(d) A solution of 450 mg. of an ozonide in 25 ml. of methylenechloride obtained in the manner described in Example 1b, by ozonizing lumista-4,22-dien-3-one, was oxidized with a solution of 200 mg. of chromic acid in 25 ml. of acetic acid overnight at 30 C. The excess quantity of chromic acid was then decomposed by stirring with 2 ml. of methanol for 30 minutes.

After dilution with water, the mixture was dissolved in diethyl ether and the ether methylene chloride extract was washed three times with 50 m1. of 2% NaOH.

These layers were combined, extracted again with diethylether to remove residues of neutral constituents. The organic acid was freed by acidifying with concentrated hydrochloric acid and dissolving in diethylether. After neutral washing with water, the mixture was dried on Na S0 filtered and finally evaporated to dryness; the yield was 240 mg. of crystalline residue. A crystallization with methanol at 5 C. yielded 150 mg. of 3-keto-retrobisnorchol-4-enic acid with a melting point of 200 to 203 C. When this acid was mixed with 3-keto-retrobisnorchol-4-enic acid as obtained by the method described in Example 10 no drop in the melting point occurred.

(e) 0.11 ml of dry, freshly distilled piperidine and 1 to 5 mg. of p-toluene sulfonic acid were added to a solution of 300 mg. of 3-keto-retro-bisnorchol-4-en22-al as obtained by ozonization of lumista-4,22-dien-3-one. This solution was then refluxed in 5 ml. of dry benzene for.3 hours under N The refluxing benzene was dried by being passed through powdered BaO in an extraction column.

After cooling, the reaction mixture was poured out into water, dissolved in diethylether and then washed adequately four times with water. The ether-benzene layer, dried on Na SO and filtered, was dried to complete dryness in vacuo. The resinous residue was stirred with 3 ml. of methanol at 15 C., cooled to -25 C. and kept at that temperature for 2 hours and crystallized. Filtering of this solution yielded 185 mg. of needles with a melting point of 88 to 93 C. of 22-(N-piperidyl)-retrobisnorchola-4,20(22)-dien-3-one.

Two recrystallizations with methanol raised the melting point of this substance to 94-96' C.

The analytical values of this pure substance were:

Found: C, 81.72%, 81.78%; H,10.64%, 10.67%; N, 3.60%, 3.66%. Calculated for C H NO: C, 81.97%; H, 10.45%; N, 3.54%.

The infrared spectrum exhibited an intensive band at 1660 cm.-' which overlapped distinctly a band with lower extinction at 1650 crnr Apart from a band at 1610 cm? a weaker band was found at 874 cm.

After a few small charges of the above-mentioned piperidino compound were produced in a similar manner, in which the final substance had a melting point of 94 to 96' C., production of several more larger charges of this compound in a difierent manner was carried out. The resultant compound which had a different melting point (114 to C.) was then obtained in large yields. Probably this effect is due to cis-trans isomerism.

This alternate method of preparing this compound were carried out as follows:

A solution of 10 g. of 3-keto-retro-bisnorchol-4-en-22-al was refluxed in 180 ml. of dry benzene with 3.8 mls. of piperidine and 30 mg. of p-toluenesulphonic acid for 3 hours under nitrogen. The refluxing benzene was dried bypassing through powdered barium oxide.

The reaction mixture was evaporated to complete dryness in vacuo, a crystalline residue of 12.3 g. being obtained. Recrystallization with 10 ml. of methanol, yielded 9.3 g. of ZZ-(N-piperidyl) retro-bisnorchola-4,20(22)- dien-3-one, melting point 98 to 107-ll1 C. A portion of this substance, which was sufiiciently pure for further processing, was recrystallized a few times with acetone for analysis until a constant melting point of 114-115 C. was attained.

The analytical values of this substance were:

6()\ max 241.5 m =22,000, [a] =123 (CHClg).

C, 81.87%, 81.98%; H, 10.49%, 10.47%; N, 3.42%, 3.63%.

The infrared spectrum of this substance differed only on details from that of the compound having a melting point of 94 to 96 C. The characteristic bands found for said substance were also found in this case.

(f) 0.5 g. of freshly melted sodium acetate was added to a solution of 1 g. of 3-keto-retro-bisnorchola-4-en-22-al, obtained as described in Example 1b, in 50 ml. of freshly distilled acetic acid anbydride. This mixture was then refluxed in a nitrogen atmosphere.

The solvent was then distilled off as far as possible under reduced pressure (about 10 minutes) and the residue obtained was dissolved in 25 ml. of chloroform. Undissolved sodium acetate was filtered off, the fiilter was washed with a small quantity of chloroform and the filtrate was diluted with the same solvent to 125 ml., 9. solution of 22-acetoxy-retro-bisnorchola-4,20(22)-dien-3-one being obtained.

(g) A solution of 300 mg. of 22-(N-piperidyl)-retrobisnorchola-4,20(22)-dien-3-one in 4.5 ml. of dry thiophene-free benzene, was added dropwise at a temperature of -5 C. to +5 C., in 45 minutes, while stirring, to a solution of 453 mg. of sodium bichromate dihydrate in 4.5 ml. of acetic acid and 3 ml. of benzene. After additional stirring for 2 hours at 0 C., 0.75 ml. of methanol was added to the dark-colored solution and stirring was continued for 30 minutes also at 0 C. This reaction mixture was then processed by pouring it out into 25 ml. of water and by extraction twice with benzene. The combined benzene extracts were then washed successively with water, 3 ml. of cold 10% NaOH solution, twice with water, 3 ml. of cold 10% hydrochloric acid solution and four times with water. The solution was then dried on Na SO filtered and evaporated to dryness producing a completely crystalline residue.

This residue was dissolved in 1 ml. of methylene chloride and 4 ml. of petroleum ether was added at boiling The infrared spectrum exhibited strong bands at 1690 cm.- and 1662 cmr and a weaker band ,at 1615 cmf (h) 0.5 .g. .of freshly melted sodium acetate vwas added to a solution of 1 g. of 3:keto-retro-bisnorcholA-en-Zbal,

obtained as described in Example 1b, in 50 ml. of freshly distilled acetic acid anhydride and the mixture was refluxed for 16 hours in a nitrogen atmosphere.

Then the solvent was distilled off as far as possible under reducedpressure (about mm. Hg) and the residue obtained was dissolved in 2-5 ml. of chloroform. The undissolved sodiumaacetate was filteredotf, the filter was washed again with a small quantity of chloroform and the .filtrate was increased with the same solvent to 150 mls. A solutibn of 22-acetoxy-retro-bisnorchola- 4,20(22)-dien-3-one was obtained. 7 I

While cooling with ice water this solution was ozonized ,for 14 minutes, 10.1- mg. of ozone being absorbed per minute. Then, after the addition of ml. of acetic acid and 2g. of zinc substance for 10 minutes,.the mixture was shaken and after filtering the solution was washed .with 10% NaOH solution and water to neutral reaction. The solution was dried on Na SO filtered and evaporated to dryness, .and then refluxed to hydrolyse any 3-enolacetate present for 45 minutes in 45 ml. of methanol and ml. of 2 N H 80 After' concentration in vacuo down to half the volume the solution was dissolved in ,diethylether. 1 The ethereal extract was washed with 10% NaOH solution and water to neutral reaction dried on Na SO evaporated to dryness and finally crystallized with 3 ml. of diethyl ether. The crystallate obtained was recrystallized with a mixture of methylene chloride and n-hexane, the yield being 113 mg. of substance with a melting pointof 160163 C. The substance dit. not exhibit a reduction in melting point with the retro-progesterone obtained as described in Example lg.

[a] :6l.5 (CHCl (mean value 0 .62.1* and -60.9).

The following compounds listed with their starting materials are prepared according to the methods of Example 1: i 7-dehydro-retroprogesterone from lumista-4,7,22-trien-3- 1 one; 6-dehydro-retro-progesterone from lumista4,6,22-trien-3- one;

-1 dehydro-retro-progesterone from lumista-l,4,22-trien-3- one;

retro'pregnad,4,6-triene-3,20-dione from lumista-l,4,6 ,22-

tetraen-3-one;

retro-pregnane-3,20-dione from lumist-22-en-3-one;

2-methyl-retro-progesterone from 2-methyllumista-4,6,22'-

trien-3-one;

6-methyl-retro-progesterone from 6-methyl-lumista-4,22-

dien-3-one;

6-fiuoro-retro-progesterone from 6-fiuoro-1umista-4,22-

dien-3-one;

6-chloro-retro-progesterone from 6-chloro-lumista-4,22-

dien-3-one;

6-hydroxy-retro-progesterone 4,22-dien-3-one;

4-chloro-retro-progesterone from 4-chloro-lumista-4,22-

. dien-3-one;

from 6-hydroxy-lumista- '1-methyl-retro-progesterone from 1-methyl-lumista-r,22-

from 2-hydroxy-lumista- .38 retropregn-5-ene-3,20-dione from one; 9-tluoro-11-hydroxy-retro-progcsterone from 9-fluoro-11- hydroxy-lumista-4,22-dien-3-one; 16-hydroxy-retro-progesterone from 16-hydroxy-lumista- 4,22-dien-3-one; 16 methyl retro progesterone from 1.6-methyl-lumista- 4,22-dien-3-one; 3hydroxy-retro pregn-5-en-Z0-one :from 3-hydroxy-lumista-5,22-diene and lumista-S ,22-dien-3- 3-1'.ydroxy-retro-pregnan-ZO-one .from 3-hydroxy-lurnist- 1t2-ene.

' Example 2 (a) To 32ml. of anhydrous ethanol there was added a mixture of 70ml. of dry benzene and 12 ml. of 2.86 sodium methoxide in dry methanol. This mixture was then .concentratedby evaporation under N about 30 ml. After cooling, While stirring, the resultant paste had added to it, 8.6 ml. of freshly distilled diethyloxalate, zsothatthe reaction mixture became .quite clear. Then, a

solution of 10 g. of retro progesterone, prepared as described in Example 1g, in 79 .mls..of dry benzene was quickly added and stirring wascontinued for about minutes. By the rapid dropwise addition of 400 ml. of dry diethylether, the .precipitation of the sodium enolate was completed. After stirring for an additional 45 min utes the resultant substance was filtered and washed adequately with ml. of dry diethylether. After drying, .for 15 hours, onconcentrated H 80 10.8 g. of yellowsodium enolate of 21Pethoxy-oxalyl-retro-progesterone was obtained.

(1;) The sodium venolate derivative thus obtained was dissolved at -20' C., while stirring in a nitrogen atmosphere, in 1 50 ml. of dry methanol. At the same temperature a solution of 5.9 g. of iodine in 210 ml. of 'dry methanol was added within 40 minutes to the reaction mixture while stirring and stirring was continued for 90 minutes. The decomposition of the iodine compound was carried out by adding 6.6 ml. of 3.56 N sodiummethoxide solution stirring was continued at 0 C. for one hour in dry methanol. From the solution obtained the reaction product was precipitated by adding dropwise, .while stirring for 45 minutes 90 ml. of water and by then adding g. of sodium chloride.

The filtered precipitate, after bein washed adequately with water, was dried overnight, the yield being 5.55 g. of 2l-iodo-retro-progesterone. 'From the filtrate, after one night, another 2.35 g. of this compound was obtained.

(0) The first fraction of 2l-iodo-retro-progesterone (Weight 5.55 g.) obtained this way, was refluxed in 200 ml. of purified dry acetone (purified with KMnO and K CO for 18 hours with 12 g. of freshly prepared potassium acetate purified by remeltiug. After evaporation of the acetone, '300 ml. of water were added and the oil separated was dissolved in methylene chloride. The extract, after drying on Na SO was evaporated to dryness (weight 1.4 g.) and chromatographed in benzene on 10 g. of neutralized A1 0 Eluation with benzene yielded 700 mg. of residue, from which after recrystallization with acetone, mg. of a substance with amelting point of 159 to 164 C. was obtained.

Corresponding acetylation of the post-fraction thus obtained of 2l-iodo-retro-progesterone (2.35 g.) yielded 2.6 g. of crude acetoxy-compound, from which 90 mg. of'solid substance with a melting point of 160-161 C. could be crystallized. Chromatography of the mother liquor as described above, after recrystallization with a'mixture of acetone, and petroleum ether (4060 C.) yielded 400 mg. with a meltingpoint of 160-163 C.

Recrystallization of the combined crystallates with acetone yielded 425 mg. with a melting point of 164167 C., from which, by recrystallization with ethanol, finally 335 mg. of pure retro-desoxycorticosterone acetate wit a melting point of 165-168 C. were obtained.

-T he analytical values of this pure substance were:

eE},,, max.=242 m =457 and 462, e242 m 17,000

Calculated for C H O (372.49): C, 74.15%; H, 8.66% Found: C, 74.03%; 74.27%; H, 8.55%; 8.77%. The infrared spectrum exhibited bands at 1226, 160 9,

' 1663, 1724 and 1751 cmf The following compounds, listed with their starting materials are prepared according to the methods used in Example 2:

2l-acetoxy-tS-dehydro-retro-progesterone from 6'-dehydroretro-progesterone;

2l-propionoxy-1,6-bisdehydro-retro-progesterone from 1,6-bisdehydro-retroprogesterone;

2l-butyroxy-retro-pregnane-3,30-dione from retropregnane-3,20-dione; h

the hemi-succinate of 2l-hydroxy-6-methyl-retroprogesterone from 6-methyl-retro-progesterone;

2l-acetoxy-9-fluoro-11-hydroxy-retro-progesterone from 9- fluoro-l 1-hydroxy-retro-progesterone;

2l-formate of 21-hydroxy-Z-methyhretro-progesterone from 2-methyl-retro-progesterone;

2l-acetoxy-l7-hydroxy-retro-progesterone from 17- hydroxy-retro-progesterone;

9-fluoro-retro-hydrocortisone 2l-aeetate from 9-fluorol l, l7dihydroxy-retro-progesterone;

2 l-acetoxyl 6-methyl-9-fluoro-l 1,17-dihydroxyretro-progesterone from 16-methyl-9-tiuoro-l1,17- dihydroxy-retro-progesterone and 21-acetoxy-9-fluoro-l 1, 16, 17-trihydroxy-retroprogesterone from 9-fiuoro-l l,16,17-trihydroxy-retro-progesterone. From all the above named compounds there can be prepared the unesterified corresponding 21-hydroxy derivatives by mild hydrolysis methods described in literature, for instance by reacting the esters with dilute alkali as potassium hydroxide or potassium bicarbonate.

Example 3 (a) A solution of 4.03 g. of bromine in 50 ml. of methylene dichloride was add id in drops while stirring at 55 C., in a nitrogen atmospl-iere to 9.6 g. of 22-(N-piperidyl)- retro-bisnorchola-4,20(22)-dien-3 one obtained as described in Example 12 and dissolved in 475 ml. of methylene dichloride. After the addition of 47 ml. of the bromine solution the mixture assumed a light-brown color, at which point the addition was stopped. Thus 22-(N- piperidyl)-20,22dibromo retro-bisnorchol-4 3n 3 one was obtained. After the reaction mixture had been warmed up to C., 60 ml. of water were added and stirring was carried out vigorously at 20 C. for 2 hours. The methylene dichloride layer then was separated and washed twice with 100 mls. of water and dried on Na SO The residue contained 20-bromo-retro-bisnorchol-4-en 3- one-22-al. To the filtered methylene dichloride solution 70 mls'. of dry pyridine were added and the methylene dichloride was distilled off in vacuo. Then dehydrobromination was carried out by heating the solution undcr N for 60 minutes, at 70 C. and then for 30 minutes at 100 C. Distilling off the pyridihe in vacuo then yielded a residue, which was dissolved in methylene dichloride and then washed successively with 2 N HCl three times with water and three times with 5% Na CO solution in water. After this, the resultant mixture was dried on Na SO filtered and evaporated to dryness. The yield was a light-brown crystalline residue with a melting point of 150 (s)--153-155 and 'f E93,, (1. max.=248 m =865 Recrystalliaztion from 30 mls. of acetone at --5" C. yielded 6 g. of 3-keto-retro-bisnorchol-4,17(20)-dien-22- at with a melting point of 154 (s)155-158 C. A small quantity of this substance was crystallized, in order to obtain a pure preparation for analysis, three times with acetone and once with ethanol. The analytical values of this purified product were as follows:

Melting point 151 (s)155-159 C. [a] =l38 (CHCl Em, A max. 248 my) =944 atmosphere to a solution of 7.7 g. of B-keto-reto-bisnorchol-4-en-22-al (obtained as described in Example 1b) in ml. of dry carbon tetrachloride, in which 3 g. of powdered calcium carbonate had been suspended. By this reaction 20-bromo-retro-bisnorchol-4-cn-3-one-22-al was formed. During the dropwise addition of the bromine solution, which took 75 minutes, a brown deposit was formed in the reaction mixture. The resultant mixture was then filtered and washed with methylene dichloride, the organic portion of the deposit being thus dissolved. The filtrate was then washed in succession twice with NaHCO; solution and twice with water, dried on Na so. and then 25 ml. of dry pyridine were added. The solution was then filtered to remove the inorganic salt and evaporated to dryness in vacuo until the final volume was about 20-30 ml. Pyridine was then added again and dehydrobromification was carried out by heating under nitrogen at 70 C., for 60 minutes and for another 30 minutes at 100 C.

The pyridine was distilled off, as far as possible, in vacuo from the dark-colored solution. Crystallization of pyridine HBr occurred. The organic constituent of this solution was dissolved in methylene dichloride and the solution obtained was successively washed twice with 2 N H 80 once with water, once with 5% NaHCO solution and once with water. This solution was then dried on Na SO and filtered by means of a small quantity of carbon, and finally evaporated to dryness, 7.15 g. of crystalline residue being thus obtained.

By recrystallization of this residue pure 3-keto-retro-bisnorchol-4,17(20)-dien-22-al was obtained.

(c) 5 g. of powdered 3-keto-retro-bisnor-chol-4, 17 (20)-dien-22-al was suspended with stirring in a solution of 8 g. of NaCN in 50 m1. of absolute methonal cooled to -20 C. To this suspension there were added by dropwise addition within about 45 minutes 7.1 mls. of glacial acetic acid while the suspension was held at20 C. Within about 2 hours, the reaction temperature was raised from 20 C. to 5 C. The white paste obtained was kept at 5 C. to 40 hours, after which it was processed by pouring it out into ml. of methylene dichloride at 0 C. and washing in succession with 75 mls. and then four times with 25 ml. of ice water and drying on Na SO at -5 C. for overnight.

A small portion of the filtered solution was evaporated to dryness. The nitrogen content of the practically colorless residue found was 4.20% (theoretical value 3.96%) and E12. (1 max. 244 m +535 (methanol) E12,, (1. max. 233 m =5l6 (diethylether) The compound thus obtained was the ZZ-HCN-addition product of 3-keto-rcto-bisnorchol-4,l7 (20)-dien-22-al. The remainder of the filtrate was ozonized at 80 C. while stirring, after 1.5 ml. of dry pyridine had been added. The duration of the ozonization was 75 minutes (per; 10 min. 2.16 mol 03), the speed of the gas being about 10% hour. 

19. A 10A-METHYL, 9B,8B,13B,14A HORMONAL STEROID OF THE PREGNANE SERIES HAVING MORE THAN 19 CARBON ATOMS IN THE MOLECULE, WHEREIN THE C17 CARBON ATOM OF THE STEROID NUCLEUS TOGETHER WITH ITS SUBSTITUENTS FROMS THE GROUP 